Cancer is one of the most important and troublesome diseases that confront mankind, and an enormous amount of research effort into the treatment thereof is being carried out. Cancer is a disease in which cells grow uncontrollably due to gene mutation, epigenetic abnormality, etc. With regard to genetic abnormalities in cancer, a large number have already been reported (e.g., Non-Patent Literature 1, etc.), and it is thought that many thereof are somehow associated with signal transduction related to cell proliferation, differentiation and survival. Furthermore, due to such genetic abnormalities, abnormalities occur in signal transduction in cells consisting of normal molecules, and this causes activation or inactivation of a specific signal cascade and can finally become one factor triggering abnormal cell proliferation. Early cancer treatment has focused on suppression of cell proliferation itself, but since such a treatment also suppresses proliferation of cells with physiologically normal proliferation, it was accompanied by side effects such as hair loss, gastrointestinal dysfunction, or bone marrow suppression. In order to reduce such side effects, development of drugs for the treatment of cancer based on a new concept such as molecularly targeted drugs that target cancer-specific genetic abnormalities or abnormalities in signal transduction is being undertaken.
As a cancer-specific genetic abnormality, abnormalities in KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) are well known. KRAS is a low molecular weight GTP-binding protein (also called a low molecular weight G protein) positioned downstream of a tyrosine kinase receptor such as EGFR (Epidermal growth factor receptor) or PDGFR (Platelet-derived growth factor receptor), and plays a part in transferring a signal related to growth or differentiation from these receptors to a downstream MAPK (Mitogen-activated protein kinase) cascade. Normal KRAS is activated via Grb2 (Growth factor receptor-bound protein 2) and SOS (Son of Sevenless) by means of tyrosine kinase activation of a receptor activated by ligand binding, and phosphorylates a MAPK such as Raf (Rapidly accelerated fibrosarcoma) so as to drive the MAPK cascade, but mutant type KRAS is constantly activated without stimulation from a receptor and continues to transmit a growth signal. It is thought that because of this, abnormal cell growth occurs.
Expression of glutathione-S-transferase (GST), which is one of the enzymes that catalyze glutathione conjugation, in particular GST-π (glutathione S-transferase pi, also called GSTP1), increases in various cancer cells, and it has been pointed out that there is a possibility that this is one factor for resistance to some anticancer agents. In fact, it is known that when GST-π antisense DNA or a GST-π inhibitor is made to act on a cancer cell line that is overexpressing GST-π and exhibiting drug resistance, the drug resistance is suppressed (Non-Patent Literatures 2 to 4). Furthermore, in a recent report, when GST-π siRNA is made to act on an androgen-independent prostate cancer cell line that is overexpressing GST-π, proliferation thereof is suppressed and apoptosis is increased (Non-Patent Literature 5). Moreover, it has been reported that, when GST-π siRNA is made to act on a cancer line that has a KRAS mutation, activation of Akt is suppressed, and autophagy increases, but there is only a medium degree of induction of apoptosis (Non-Patent Literature 6), and Patent Literature 1 describes an apoptosis-inducing agent, etc. that includes a drug that suppresses GST-π and a drug that suppresses autophagy as active ingredients.
However, there has so far been hardly any clarification of the relationship between GST-π and cell proliferation or apoptosis, the molecular mechanism of GST-π, and the role, etc., of GST-π in various types of intracellular signal transduction. Intracellular signal transduction is very complicated; one molecule may influence the effect of a plurality of molecules, or conversely one molecule may be influenced by a plurality of molecules, when the effect of a certain molecule is inhibited, another signal cascade may be activated, and an expected effect often cannot be obtained. Therefore, it is necessary to elucidate the complicated cell signal transduction mechanism in order to develop superior molecularly targeted drugs, but only a very small part of the mechanism has been elucidated in many years of research, and further research effort is needed.